Browse
Submit Data
Databases
API
Help

Dataset Information

21 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Pathophysiology and inhibition of IL-23 signaling in psoriatic arthritis: A molecular insight.

ABSTRACT: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis of unknown etiology, and currently the cellular and molecular interactions that dictate its pathogenesis remain elusive. A role of the interleukin-23 (IL-23)/IL-23R (IL-23 receptor) interaction in the development of psoriasis and PsA is well established. As IL-23 regulates the differentiation and activation of innate and adaptive immunity, it pertains to a very complex pathophysiology involving a plethora of effectors and transducers. In this review, we will discuss recent advances on the cellular and molecular pathophysiological mechanisms that regulate the initiation and progression of PsA as well as new therapeutic approaches for IL-23/IL-23R targeted therapeutics.

SUBMITTER: Nguyen CT

PROVIDER: S-EPMC6401348 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Pathophysiology and inhibition of IL-23 signaling in psoriatic arthritis: A molecular insight.

Nguyen Cuong Thach CT Bloch Yehudi Y Składanowska Katarzyna K Savvides Savvas N SN Adamopoulos Iannis E IE

Clinical immunology (Orlando, Fla.) 20180906

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis of unknown etiology, and currently the cellular and molecular interactions that dictate its pathogenesis remain elusive. A role of the interleukin-23 (IL-23)/IL-23R (IL-23 receptor) interaction in the development of psoriasis and PsA is well established. As IL-23 regulates the differentiation and activation of innate and adaptive immunity, it pertains to a very complex pathophysiology involving a plethora of effectors and transducers. ...[more]

PMID: 30196070

Similar Datasets

The IL-17/IL-23 Axis and Its Genetic Contribution to Psoriatic Arthritis.

Project description:Psoriatic arthritis (PsA) is a chronic inflammatory disease belonging to the family of spondyloarthropathies (SpA). PsA commonly aggravates psoriasis of the skin and frequently manifests as an oligoarthritis with axial skeletal involvement and extraarticular manifestations including dactylitis, enthesitis, and uveitis. The weight of genetic predisposition to psoriasis and PsA is illustrated by the concordance rates in monozygotic twins which clearly demonstrate that genomics is insufficient to induce the clinical phenotype. The association of PsA with several single nucleotide polymorphisms (SNPs) at the IL23R locus and the involvement of Th17 cells in the immunopathogenesis of PsA clearly put the IL-23/IL-17 axis in the spotlight. The IL-23 and IL-17 cytokines have a pivotal role in the chronic inflammation of the synovium in PsA and are also prominent in the skin lesions of those with PsA. In this review, we focus on the genetic association of the IL-23/IL-17 axis with PsA and the contribution of these master cytokines in the pathophysiology of the disease, highlighting the main cell types incriminated in PsA and their specific role in the peripheral blood, lesional skin and joints of patients. We then provide an overview of the approved biologic drugs targeting the IL-23/IL-17 axis and discuss the advantages of genetic stratification to enhance personalized therapies in PsA.

| S-EPMC7871349 | biostudies-literature

Mini Review: New Treatments in Psoriatic Arthritis. Focus on the IL-23/17 Axis.

Project description:Psoriasis, an inflammatory skin disease, and psoriatic arthritis (PsA), an inflammatory arthritis, share clinical, genetic, and pathogenic factors and may be summed as one disease, the psoriatic disease. Interleukin (IL)-17 plays a major role in the development of both psoriasis and PsA. IL-23 is important in the proliferation and maintenance of IL-17, and therefore, cytokines of the IL-23/IL-17 axis attracted much interest as therapeutic targets in psoriasis and PsA. Therapeutic agents targeting the IL-23/IL-17 axis have been proven to be very effective in psoriasis and PsA, some are already in the therapeutic armamentarium and others are in the development. Some agents, target IL-23 and others IL-17 and include anti-IL-12/IL-23 p40 (ustekinumab, briankizumab), anti-IL-23p19 (guselkumab, tildrakizumab, risankizumab, brazikumab, mirikizumab), anti-IL-17A (secukinumab, ixekizumab), dual anti-IL-17A and anti-IL-17F (bimekizumab), or anti-IL-17 receptor (brodalumab) monoclonal antibodies. Janus tyrosine kinase(JAK) inhibitors also directly affect IL-23 and, thus, IL-17. After the first-generation pan-JAK inhibitors have been shown efficacy (tofacitinib, baricitinib), new-generation selective JAK inhibitors (filgotinib, upadacitinib) are under investigation in psoriasis and PsA.

| S-EPMC6691125 | biostudies-literature

Targeting IL-17 in psoriatic arthritis.

Project description:Psoriatic arthritis (PsA) is a chronic and progressive inflammatory arthritis intimately associated with psoriasis, and can be an impairing disease that leads to reduced quality of life and significant morbidity. Treatment often requires TNF antagonists, yet many patients with PsA are not responsive to the standard anti-TNF therapies. The interleukin-17 (IL-17)/IL-17 receptor (IL-17R) family has recently been implicated in the pathogenesis of PsA and psoriasis. Much enthusiasm has been generated for the development of biologics that target the IL-17 signaling pathway directly or indirectly, many of which have produced striking results in the setting of psoriasis and PsA. Herein, we review the role of IL-17 and the IL-17 receptor (IL-17R) in the pathogenesis of PsA, as well as the clinical evidence for IL-17 and IL-17R targeted therapeutics.

| S-EPMC5741341 | biostudies-literature

Use of IL-23 Inhibitors for the Treatment of Plaque Psoriasis and Psoriatic Arthritis: A Comprehensive Review.

Project description:Psoriasis is a common inflammatory skin disease with multiple comorbidities, including psoriatic arthritis and coronary artery disease, that can severely impact an individual's quality of life and daily functioning. In recent years, enhanced understanding of the pathogenesis of psoriasis, especially the role of T helper 17 cells, has resulted in the development of new classes of biologic drugs targeting modulators along its disease pathway. Among these, inhibitors of interleukin-23 (e.g., ustekinumab, guselkumab, tildrakizumab, and risankizumab) have emerged as safe and effective options for the treatment of moderate-to-severe plaque psoriasis; ustekinumab and guselkumab have additionally been approved to treat psoriatic arthritis. Selective interleukin-23 inhibitors require less frequent dosing than interleukin-17 inhibitors and may possess a more favorable risk profile without an increased risk of candidiasis or inflammatory bowel disease. Overall, these highly effective medications are contributing to a rising standard for psoriasis outcomes through resolution of skin lesions and joint manifestations and improvement of patient quality of life.

| S-EPMC7727454 | biostudies-literature

Adenoviral gene transfer of a single-chain IL-23 induces psoriatic arthritis-like symptoms in NOD mice.

Project description:Previously, we demonstrated that intratumoral delivery of adenoviral vector encoding single-chain (sc)IL-23 (Ad.scIL-23) was able to induce systemic antitumor immunity. Here, we examined the role of IL-23 in diabetes in nonobese diabetic mice. Intravenous delivery of Ad.scIL-23 did not accelerate the onset of hyperglycemia but instead resulted in the development of psoriatic arthritis. Ad.scIL-23-treated mice developed erythema, scales, and thickening of the skin, as well as intervertebral disc degeneration and extensive synovial hypertrophy and loss of articular cartilage in the knees. Immunological analysis revealed activation of conventional T helper type 17 cells and IL-17-producing γδ T cells along with a significant depletion and suppression of T cells in the pancreatic lymph nodes. Furthermore, treatment with anti-IL-17 antibody reduced joint and skin psoriatic arthritis pathologies. Thus, these Ad.scIL-23-treated mice represent a physiologically relevant model of psoriatic arthritis for understanding disease progression and for testing therapeutic approaches.-Flores, R. R., Carbo, L., Kim, E., Van Meter, M., De Padilla, C. M. L., Zhao, J., Colangelo, D., Yousefzadeh, M. J., Angelini, L. A., Zhang, L., Pola, E., Vo, N., Evans, C. H., Gambotto, A., Niedernhofer, L. J., Robbins, P. D. Adenoviral gene transfer of a single-chain IL-23 induces psoriatic arthritis-like symptoms in NOD mice.

| S-EPMC6662986 | biostudies-literature

The Molecular Pathophysiology of Psoriatic Arthritis-The Complex Interplay Between Genetic Predisposition, Epigenetics Factors, and the Microbiome.

Project description:Psoriasis is a symmetric autoimmune/inflammatory disease that primarily affects the skin. In a significant proportion of cases, it is accompanied by arthritis that can affect any joint, the spine, and/or include enthesitis. Psoriasis and psoriatic arthritis are multifactor disorders characterized by aberrant immune responses in genetically susceptible individuals in the presence of additional (environmental) factors, including changes in microbiota and/or epigenetic marks. Epigenetic changes can be heritable or acquired (e.g., through changes in diet/microbiota or as a response to therapeutics) and, together with genetic factors, contribute to disease expression. In psoriasis, epigenetic alterations are mainly related to cell proliferation, cytokine signaling and microbial tolerance. Understanding the complex interplay between heritable and acquired pathomechanistic factors contributing to the development and maintenance of psoriasis is crucial for the identification and validation of diagnostic and predictive biomarkers, and the introduction of individualized effective and tolerable new treatments. This review summarizes the current understanding of immune activation, genetic, and environmental factors that contribute to the pathogenesis of psoriatic arthritis. Particular focus is on the interactions between these factors to propose a multifactorial disease model.

| S-EPMC8047476 | biostudies-literature

Role of the IL-23/IL-17 Axis in Psoriasis and Psoriatic Arthritis: The Clinical Importance of Its Divergence in Skin and Joints.

Project description:Psoriasis is a chronic systemic inflammatory disease causing erythematosus and scaly skin plaques; up to 30% of patients with psoriasis develop Psoriatic Arthritis (PsA), which is characterised by inflammation and progressive damage of the peripheral joints and/or the spine and/or the entheses. The pathogenic mechanisms driving the skin disorder in psoriasis and the joint disease in PsA are sustained by the activation of inflammatory pathways that can be overlapping, but also, at least partially, distinct. Cytokines members of the IL-23/IL-17 family, critical in the development of autoimmunity, are abundantly expressed within the cutaneous lesions but also seem to be involved in chronic inflammation and damage of the synovium though, as it will be here discussed, not in all patients. In this review, we will focus on the state of the art of the molecular features of psoriatic skin and joints, focusing on the specific role of the IL-23/IL-17 pathway in each of these anatomical districts. We will then offer an overview of the approved and in-development biologics targeting this axis, emphasising how the availability of the "target" in the diseased tissues could provide a plausible explanation for the heterogeneous clinical efficacy of these drugs, thus opening future perspective of personalised therapies.

| S-EPMC5855752 | biostudies-literature

IL-36γ Is a Strong Inducer of IL-23 in Psoriatic Cells and Activates Angiogenesis.

Project description:The IL-1 family member cytokine IL-36γ is recognised as key mediator in the immunopathology of psoriasis, hallmarks of which involve the activation of both resident and infiltrating inflammatory myeloid cells and aberrant angiogenesis. This research demonstrates a role for IL-36γ in both myeloid activation and angiogenesis. We show that IL-36γ induces the production of psoriasis-associated cytokines from macrophages (IL-23 and TNFα) and that this response is enhanced in macrophages from psoriasis patients. This effect is specific for IL-36γ and could not be mimicked by other IL-1 family cytokines such as IL-1α. IL-36γ was also demonstrated to induce endothelial tube formation and branching, in a VEGF-A-dependent manner. Furthermore, IL-36γ-stimulated macrophages potently activated endothelial cells and led to increased adherence of monocytes, effects that were markedly more pronounced for psoriatic macrophages. Interestingly, regardless of stimulus, psoriasis monocytes showed increased adherence to both the stimulated and unstimulated endothelium when compared with monocytes from healthy individuals. Collectively, these findings show that IL-36γ has the potential to enhance endothelium directed leucocyte infiltration into the skin and strengthen the IL-23/IL-17 pathway adding to the growing evidence of pathogenetic roles for IL-36γ in psoriatic responses. Our findings also point to a cellular response, which could potentially explain cardiovascular comorbidities in psoriasis in the form of endothelial activation and increased monocyte adherence.

| S-EPMC5834930 | biostudies-literature

Proteinase-Mediated Macrophage Signaling in Psoriatic Arthritis.

Project description:ObjectiveMultiple proteinases are present in the synovial fluid (SF) of an arthritic joint. We aimed to identify inflammatory cell populations present in psoriatic arthritis (PsA) SF compared to osteoarthritis (OA) and rheumatoid arthritis (RA), identify their proteinase-activated receptor 2 (PAR2) signaling function and characterize potentially active SF serine proteinases that may be PAR2 activators.MethodsFlow cytometry was used to characterize SF cells from PsA, RA, OA patients; PsA SF cells were further characterized by single cell 3'-RNA-sequencing. Active serine proteinases were identified through cleavage of fluorogenic trypsin- and chymotrypsin-like substrates, activity-based probe analysis and proteomics. Fluo-4 AM was used to monitor intracellular calcium cell signaling. Cytokine expression was evaluated using a multiplex Luminex panel.ResultsPsA SF cells were dominated by monocytes/macrophages, which consisted of three populations representing classical, non-classical and intermediate cells. The classical monocytes/macrophages were reduced in PsA compared to OA/RA, whilst the intermediate population was increased. PAR2 was elevated in OA vs. PsA/RA SF monocytes/macrophages, particularly in the intermediate population. PAR2 expression and signaling in primary PsA monocytes/macrophages significantly impacted the production of monocyte chemoattractant protein-1 (MCP-1). Trypsin-like serine proteinase activity was elevated in PsA and RA SF compared to OA, while chymotrypsin-like activity was elevated in RA compared to PsA. Tryptase-6 was identified as an active serine proteinase in SF that could trigger calcium signaling partially via PAR2.ConclusionPAR2 and its activating proteinases, including tryptase-6, can be important mediators of inflammation in PsA. Components within this proteinase-receptor axis may represent novel therapeutic targets.

| S-EPMC7982406 | biostudies-literature

Angiogenesis Dysregulation in Psoriatic Arthritis: Molecular Mechanisms.

Project description:There is evidence that psoriatic arthritis is closely linked to angiogenesis. Morphological changes described in blood vessels of psoriatic arthritis joints suggest the presence of a dysregulated angiogenesis resulting in the formation of immature vessels. Even if the reason of this inefficient angiogenesis is still unclear, an imbalance between angiogenic and antiangiogenic factors is probably responsible for inducing a dysregulated angiogenesis in psoriatic arthritis, which seems to be involved in its pathogenesis and clinical features. Nevertheless, among chronic arthritides, while angiogenesis in rheumatoid arthritis has been largely studied with a great amount of literature data, limited data on angiogenesis role in psoriatic arthritis are available. This review article is focused on current knowledge on the mechanisms responsible for dysregulated angiogenesis in psoriatic arthritis.

| S-EPMC5539937 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data